The pathological hallmark of many periodontal diseases is the accumulation of large numbers of neutrophils within oral mucosal tissue, and in particular, at the level of the epithelium. At present, little is known about the molecular events and regulatory pathways associated with neutrophil (PMN) recruitment to, and transmigration across, oral epithelia. As work in progress, we have defined a model to analyze potential regulatory sites in PMN-oral epithelial interactions in vitro. Results from these studies suggest that PMN utilize a previously undescribed pathway to traverse oral epithelial monolayers, and that this pathway is regulated by metabolically stable eicosanoids derived from transcellular biosynthesis of arachidonic acid (lipoxins). Further studies indicate that oral epithelial-PMN interactions are modulated by paracrine factors endogenous to the inflamed oral mucosa. The overall goal of this proposal is to examine protein and lipid mediators of PMN-oral epithelial interactions and to define potential targets for development of novel small molecule therapeutics. Three specific aims are proposed to accomplish this overall goal: As a first specific aim, we will dissect lipoxin interaction pathways during PMN-oral epithelial adhesion and transmigration, and establish the role of epithelial chemokine generation during these modeled inflammatory events. Specific aim two will define the existence of novel PMN adhesion molecules expressed on oral epithelia and elucidate molecular determinants for these molecules. In specific aim three, we will define the impact of paracrine mediators on oral epithelial function and PMN- epithelial interactions. Results at each juncture will be integrated with other programmatic projects to address the more global goal of defining novel targets for the development of experimental therapeutics to heal oral mucosal inflammatory disease.